Sequential Seyferth-Gilbert/CuAAC Reactions: Application to the One-Pot Synthesis of Triazoles from Aldehydes

Abstract

A reliable and operationally simple one-pot reaction for a one-carbon homologation of various aldehydes followed by a Cu-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) is reported. 1,4-Disubstituted 1,2,3-triazoles are obtained in good to excellent yields from a variety of readily available aldehydes without the need for isolation of the alkyne intermediates. The reaction has a broad scope, allows the formation of new bioconjugates and is applied for the synthesis of new boronic acid based fluorescent sensors.

click chemistry - 1,2,3-triazole - Bestmann-Ohira reagent - bioconjugation - boronic acids

References and Notes

1 Rostovtsev VV. Green LG. Fokin VV. Sharpless KB. Angew. Chem. Int. Ed.  2002,  41:  2596 

2 Tornoe CW. Christensen C. Meldal M. J. Org. Chem.  2002,  67:  3057 

3 Wu P. Fokin VV. Aldrichimica Acta  2007,  40:  7 

4 Bock VD. Hiemstra H. van Maarseveen JH. Eur. J. Org. Chem.  2005,  51 

5 Kolb HC. Finn MG. Sharpless KB. Angew. Chem. Int. Ed.  2001,  40:  2004 

6 Speers AE. Cravatt BF. Chem. Biol.  2004,  11:  535 

7 Kosiova I. Kovackova S. Kois P. Tetrahedron  2007,  63:  312 

8 Gierlich J. Burley GA. Gramlich PME. Hammond DM. Carell T. Org. Lett.  2006,  8:  3639 

9 Bouillon C. Meyer A. Vidal S. Jochum A. Chevolot Y. Cloarec JP. Praly JP. Vasseur JJ. Morvan F. J. Org. Chem.  2006,  71:  4700 

10 Perez-Balderas F. Ortega-Munoz M. Morales-Sanfrutos J. Hernandez-Mateo F. Calvo-Flores FG. Calvo-Asin JA. Isac-Garcia J. Santoyo-Gonzalez F. Org. Lett.  2003,  5:  1951 

11 Kuijpers BHM. Groothuys S. Keereweer AR. Quaedflieg P. Blaauw RH. van Delft FL. Rutjes F. Org. Lett.  2004,  6:  3123 

12 Odlo K. Hoydahl EA. Hansen TV. Tetrahedron Lett.  2007,  48:  2097 

13 Chittaboina S. Xie F. Wang Q. Tetrahedron Lett.  2005,  46:  2331 

14 Kacprzak K. Synlett  2005,  943 

15 Feldman AK. Colasson B. Fokin VV. Org. Lett.  2004,  6:  3897 

16 Andersen J. Bolvig S. Liang XF. Synlett  2005,  2941 

17 Barral K. Moorhouse AD. Moses JE. Org. Lett.  2007,  9:  1809 

18 Beckmann HSG. Wittmann V. Org. Lett.  2007,  9:  1 

19 Nepogodiev SA. Dedola S. Marmuse L. de Oliveira MT. Field RA. Carbohydr. Res.  2007,  342:  529 

20 Seela F. Sirivolu VR. Helv. Chim. Acta  2007,  90:  535 

21 Zheng SL. Reid S. Lin N. Wang BH. Tetrahedron Lett.  2006,  47:  2331 

22

A quick search in the Aldrich catalogue (sigma-aldrich.com) found 269 commercial alkynes vs. 870 aldehydes.

23 Ohira S. Synth. Commun.  1989,  19:  561 

24 Muller S. Liepold B. Roth GJ. Bestmann HJ. Synlett  1996,  521 

25

General Experimental Procedure: The aldehyde (2 mmol), 2-oxopropyldiazodimethyl phosphonate (4 mmol) and K₂CO₃ (6 mmol) were suspended in MeOH-THF (1:1; 4 mL) under an argon atmosphere. The reaction mixture was stirred at r.t. until TLC showed the reaction to be complete (2-24 h, in some cases another 0.5 equiv of the reagent was needed to reach completion). When the starting aldehyde was completely converted into the intermediate alkyne, CuI (0.4 mmol) and the azide (2 mmol) were added, and the reaction mixture was stirred at r.t. The progress of the reaction was followed by TLC (2-12 h). The solvents were removed in vacuo and the residue was dissolved in EtOAc (20 mL) and H₂O (20 mL). The aqueous layer was washed with EtOAc (2 × 20 mL). The organic phase was washed with a sat. solution of NH₄Cl (20 mL), brine (20 mL) and dried over anhyd Na₂SO₄. The solvent was removed in vacuo and the crude product was further purified by column chromatography (n-hexane-EtOAc).
Characterization Data for Selected Compounds: 1-{2′-Deoxy-4′-[1-(pyren-1-ylmethyl)-1,2,3-triazol-4-yl]-3′- O - tert -butyldimethylsilyl-β-d -erythrofurano-syl}thymine (Table 1, entry 6): yield: 73%; mp 125-126 °C; R _f 0.53 (n-hexane-EtOAc, 5:5). ¹H NMR (300 MHz, CDCl₃): δ = 0.03 (s, 3 H), 0.13 (s, 3 H), 0.75 (s, 9 H), 1.69 (s, 3 H), 2.20-2.29 (m, 1 H), 2.48-2.57 (m, 1 H), 4.66-4.68 (m, 1 H), 4.79 (d, J = 2.6 Hz, 1 H), 6.29 (s, 2 H), 6.44 (t, J = 5.9 Hz, 1 H), 7.31 (s, 1 H), 7.64 (s, 1 H), 7.99-8.16 (m, 9 H).¹³C NMR (75 MHz, CDCl₃): δ = 4.8, 4.9, 12.4, 25.6, 40.4, 52.5, 75.8, 80.8, 85.7, 111.1, 121.7, 122.4, 124.5, 125.0, 125.2, 125.9, 126.1, 126.2, 126.5, 127.2, 127.8, 128.5, 129.3, 129.4, 130.5, 131.2, 132.3, 136.3, 140.0, 150.2, 163.4. MS (ESI⁺): m/z (%) = 608 (100) [M + H]⁺. HRMS (FAB⁺, NBA): m/z calcd for C₃₄H₃₈N₅O₄Si (M + H⁺): 608.2693; found: 608.2712.
(2 S ,3 R )- tert -Butyl-2-(benzyloxycarbonylamino)-3-[4-(pyren-1-yl)-1,2,3-triazol-1-yl]butanoate (Table 1, entry 10): yield: 75%; mp 81-83 °C; [α]²⁰ +12° (c = 1, CHCl₃); R _f 0.10 (n-hexane-EtOAc, 8:2). ¹H NMR (300 MHz, CDCl₃): δ = 1.49 (s, 9 H), 1.83 (d, J = 6.8 Hz, 3 H), 4.85-4.89 (dd, J = 4.8, 8.5 Hz, 1 H), 5.11 (m, 1 H), 5.17 (s, 2 H), 5.90 (d, J = 8.3 Hz, 1 H), 7.18-7.31 (m, 3 H), 7.76-7.78 (m, 2 H), 8.00-8.14 (m, 9 H), 8.67 (d, J = 9.3 Hz, 1 H).¹³C NMR (75 MHz, CDCl₃): δ = 21.4, 27.9, 58.3, 58.8, 84.0, 122.0, 124.7, 124.8, 125.2, 125.4, 126.1, 126.3, 127.2, 127.4, 127.8, 128.1, 128.2, 128.3, 128.5, 128.6, 129.6, 130.9, 131.3, 131.4, 139.3, 143.3, 147.2, 155.9, 167.9. MS (ESI⁺): m/z (%) = 561 (100) [M + H]⁺. HRMS (ESI⁺): m/z calcd for C₃₄H₃₃N₄O₄ (M + H⁺): 561.2502; found: 561.2480.
1-{2′-Deoxy-4′-[1-(2′,3′,4′,6′-tetra- O -benzyl-β-d -gluco-pyranosyl)[1,2,3]triazol-4-yl]-3′- O - tert -butyldimethyl-silyl-β-d -erythrofuranosyl}thymine (Table 1, entry 11): yield: 80%; mp 80-83 °C; R _f 0.51 (n-hexane-EtOAc, 5:5). ¹H NMR (300 MHz, CDCl₃): δ = 0.00 (s, 3 H), 0.05 (s, 3 H), 0.88 (s, 9 H), 1.84 (s, 3 H), 2.34-2.63 (m, 2 H), 3.78-3.89 (m, 2 H), 4.05-4.18 (m, 2 H), 4.47-4.96 (m, 10 H), 5.61 (d, J = 9.0 Hz, 1 H), 6.53 (t, J = 6.80 Hz, 1 H), 6.92-6.96 (m, 2 H), 7.16-7.33 (m, 20 H), 7.64 (s, 1 H), 7.82 (s, 1 H), 9.10 (br s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = -4.79, -4.76, 12.5, 17.9, 25.6, 40.4, 68.3, 73.6, 74.8, 75.2, 75.8, 77.2, 77.5, 78.1, 80.2, 80.9, 85.5, 85.8, 87.6, 111.2, 122.1, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.4, 128.5, 136.6, 136.8, 137.6, 138.0, 146.1, 150.6, 163.9. MS (ESI⁺): m/z (%) = 916.3 (100) [M + H]⁺. HRMS (ESI⁺): m/z calcd for C₅₁H₆₂N₅O₉Si (M + H⁺): 916.4317; found: 916.4327.
3′-[4-(2′-Deoxy-3′- O - tert -butyldimethylsilyl-1′-thyminyl-β-d -erythrofuranos-4′-yl)-1,2,3-triazol-1-yl]thymidine (Table 1, entry 13): yield: 85%; mp 139-140 °C; R _f 0.09 (CH₂Cl₂-EtOAc, 5:5). ¹H NMR (300 MHz, CDCl₃): δ = 0.06 (2 × s, 6 H), 0.87 (s, 9 H), 1.92 (s, 3 H), 1.95 (s, 3 H), 2.33-2.71 (m, 2 H), 2.94-3.09 (m, 2 H), 3.82-4.12 (m, 2 H), 4.44-4.46 (m, 1 H), 4.71-4.74 (m, 1 H), 4.97 (d, J = 3.01 Hz, 1 H), 5.43-5.49 (m, 1 H), 6.21 (t, J = 6.55 Hz, 1 H), 6.36 (t, J = 6.4 Hz, 1 H), 7.41 (s, 1 H), 7.65 (s, 1 H), 7.80 (s, 1 H), 8.61 (br s, 1 H), 8.64 (br s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 4.83, 12.4, 12.5, 14.2, 25.7, 36.5, 39.8, 59.1, 60.6, 61.2, 76.2, 81.0, 85.3, 87.5, 88.4, 111.2, 122.3, 137.6, 137.7, 146.0, 150.6, 150.8, 164.1, 164.2. MS (ESI⁺): m/z (%) = 618 (100) [M + H]⁺. HRMS (FAB⁺, NBA): m/z calcd for C₂₇H₃₉N₇O₈Si (M + H⁺): 618.2708; found: 618.2682.

26 Yang W. Gao X. Wang B. Boronic Acids   Hall DG. Wiley-VCH; Weinheim: 2005.  Chap. 13.

27 James TD. Boronic Acids   Hall DG. Wiley-VCH; Weinheim: 2005.  Chap. 12.

28 Luvino D. Smietana M. Vasseur JJ. Tetrahedron Lett.  2006,  47:  9253 

29

Characterization Data for Selected Compounds: 1-Benzyl-4-[3-(4,4,5,5-tetramethyl-1,3-dioxa-2-borolan-2-yl)phenyl]-1,2,3-triazole (Table 2, entry 1): yield: 30%; white solid; mp 172-173 °C; R _f 0.24 (n-hexane-EtOAc, 8:2). ¹H NMR (300 MHz, CDCl₃): δ = 1.22 (s, 12 H), 5.44 (s, 2 H), 7.14-7.33 (m, 5 H), 7.25 (s, 1 H), 7.59 (s, 1 H), 7.64 (m, 1 H), 7.92 (m, 1 H), 7.97 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 22.6, 52.0, 81.7, 117.4, 125.8, 126.1, 126.4, 126.5, 126.9, 127.8, 129.7, 132.3, 132.5, 146.0. MS (ESI⁺): m/z (%) = 362.2 (100) [M + H]⁺. HRMS (ESI⁺): m/z calcd for C₂₁H₂₅BN₃O₂ (M + H⁺): 362.2040; found: 362.2037.
1-(Pyren-1-ylmethyl)-4-[4-(4,4,5,5-tetramethyl-1,3-dioxa-2-borolan-2-yl)phenyl]-1,2,3-triazole (Table 2, entry 4): yield: 55%; mp 168-170 °C; R _f 0.14 (n-hexane-EtOAc, 8:2). ¹H NMR (400 MHz, CDCl₃): δ = 1.23 (s, 12 H), 6.21 (s, 2 H), 7.22 (d, J = 7.9 Hz, 2 H), 7.44-7.74 (m, 3 H), 7.92-8.19 (m, 8 H), 8.17 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 24.8, 55.3, 83.8, 119.9, 121.9, 124.8, 125.9, 126.0, 126.5, 127.2, 127.8, 128.4, 128.7, 129.2, 129.4, 130.6, 131.2, 132.3, 132.9, 135.2, 139.1, 143.6, 147.9. MS (ESI⁺): m/z (%) = 486 (100) [M + H]⁺. HRMS (ESI⁺): m/z calcd for C₃₁H₂₉BN₃O₂ (M + H⁺): 486.2353; found: 486.2378.